Device Closure of Hemodynamically Significant Patent Ductus Arteriosus in Premature Infants

The patent ductus arteriosus is a very common condition in preterm infants, and a hemodynamically significant patent ductus arteriosus increases morbidity and mortality in these vulnerable patients. However, despite numerous randomized controlled trials, there is no consensus regarding management. Medical therapy is typically offered as first-line treatment, although it yields limited success and carries the potential for severe adverse events. In recent years, there has been rapid development in transcatheter patent ductus arteriosus closure primary with the use of the Amplatzer Piccolo Occluder, and this has gained widespread acceptance as a safe and effective alternative to surgical ligation in extremely low-birth-weight infants weighing over 700 g. This article aims to provide an appraisal of the patient selection process, a step-by-step procedural guide, and a comprehensive review of the outcomes associated with this approach.

morbidity, supporting a more active PDA treatment approach.Therefore, PDA closure may be indicated in any preterm infant with a hsPDA.Cyclo-oxygenase inhibitors and/or paracetamol are typically used as initial medical treatment exhibiting a moderate success rate of 60 to 70%.However, their use carries the risk of major adverse events (MAE), such as bleeding, NEC, renal impairment, and developmental delay. 5Surgical PDA ligation has traditionally been the sole nonpharmacological option; however, transcatheter PDA closure has emerged as a safe and effective alternative for infants who have not responded to medical management nor have contraindications to it.The Amplatzer Piccolo Occluder (APO, Abbott Structural Heart) received Food and Drug Administration (FDA) and Conformité Européennemark approval in 2019 for PDA closure in infants weighing more than 700 g and older than 3 days of life, with an excellent success rate and a low incidence of periprocedural complications when performed in experienced teams. 6It has now become the preferred therapeutic option over surgical ligation in many expert centers worldwide.This article aims to provide an overview of the case and device selection process, a step-bystep description of the procedure, and a contemporary review of its outcomes.

DEFINITIONS: EPIDEMIOLOGY
A PDA is defined as a failure of the ductus arteriosus to close within 72 hours after birth.It is a common condition in very low-birth-weight (VLBW, birth weight <1,500 g) and extremely low-birth-weight (ELBW) (birth weight <1,000 g) infants, with a higher incidence in lower gestational age.It is reported in around 50% of the infants born <28 weeks gestation and/or at a birth weight <1,000 g. 7 A comprehensive definition of a hsPDA would encompass the magnitude of the ductal shunt and the hemodynamic impact, integrating various parameters such as PDA size, shunt volume, cardiovascular load, and end-organ perfusion.This definition would offer guidance on which patients requirement treatment and the optimal timing for intervention.Since the first staging system proposed by McNamara et al. 8 in 2007, several PDA scoring systems have been developed for risk stratification, to help clinicians identify higher-risk infants who may benefit from PDA closure. 8,9The definition of a hsPDA is based on a staging system that incorporates both clinical and echocardiographic criteria.Clinical indicators include the need for respiratory support, mechanical ventilation or high-frequency ventilation, feeding intolerance or abdominal distension resembling NEC, acute renal failure, hemodynamic instability, or metabolic acidosis.Echocardiographic criteria include a transductal diameter >1.5 mm, left heart volume loading, decreased, absent, or reversed diastolic flow in the superior mesenteric artery, middle cerebral artery, or renal artery and unrestrictive pulsatile transductal flow. 1,5,8,9These criteria are detailed in Table 1.This purpose of this staging system for PDA categorization is to facilitate triage and case prioritization, particularly for the most critically ill infants.However, there is currently no standardized consensus in defining a hemodynamically significant PDA in a preterm infant.

CONTRA INDICATIONS
PDA closure may be indicated in any symptomatic preterm infant with a hemodynamically significant PDA.There are a few contraindications to HIGHLIGHTS Surgical ligation has traditionally been the standard of care for hemodynamically significant patent ductus arteriosus in extremely low-birth-weight premature infants.However, transcatheter closure is emerging as a safe and effective alternative in experienced centers.
Optimal patient selection and management requires multidisciplinary involvement.
The procedure relies on close collaboration between the interventionalist and the sonographer performing the transthoracic echocardiogram, as it is essential in confirming the indication for closure, choosing the right device and guiding appropriate device placement.
Modified techniques including bedside procedures and fluoroscopy-free approaches, combined with the increasing expertise of interventionalists and echocardiographers, will further enhance the safety and broaden the application of transcatheter patent ductus arteriosus closure in these extremely vulnerable patients.2. High-frequency ventilation does not compromise the safe and efficient placement of devices. 10Renal failure, cerebral hemorrhage, or enterocolitis does not preclude the procedure, providing there is no sepsis.The APO device is not recommended for use in the very large (ie, >4 mm minimal ductal diameter) PDA, which may necessitate considering exemption or even off-label use of alternative devices, such as the Amplatzer Vascular Plug-II (AVP-II, Abbott).

CASE PLANNING
The indication for the device closure of a PDA in an ELBW infant is agreed upon by consensus among the treating neonatologists and pediatric interventional cardiologists.The decision is informed by a comprehensive pre-operative assessment encompassing demographic parameters, careful review of the current clinical situation, strategies for potential clinical optimization, and detailed echocardiographic evaluation (Figure 2).Once the indication of PDA closure is jointly agreed, the patient is transferred to the neonatal intensive care unit (NICU) at the institution where the procedure will be performed 1 day prior to the procedure.A comprehensive clinical assessment and echocardiogram is conducted to assess for any contraindications and parental informed consent is obtained.Hemoglobin and platelets are optimized as required.Intravascular access is secured before transfer to the catheterization laboratory to reduce the time spent outside the NICU.Two intravenous lines are established, for procedural sedation and resuscitation if required.If the patient is not already on mechanical ventilation, intubation is performed in the NICU.Mechanical ventilation is optimized to allow as much as possible respiratory stability during the procedure.Some institutions attempt a trial of conventional ventilation the day before the procedure in neonates dependent on high-frequency ventilation. 10The infant is transferred to the catheterization laboratory by the treating NICU team with the neonatal ventilator, avoiding disconnection from the ventilator for procedural purpose. 11,12anscatheter PDA closure is routinely performed in the catheterization laboratory worldwide, although successful bedside interventions have been reported with the use of a portable C-arm fluoroscopy system or solely by echocardiographic guidance (ie, without fluoroscopy).Severe left heart pressure loading (eg, E/A ratio >1.5)

Reversal of end-diastolic flow in superior mesenteric artery, middle cerebral artery, or renal artery
Patients should be assigned both a clinical (C1 to C4) and an echocardiographic (E1 to E4) stage.Adapted From McNamara et al. 8 BP ¼ blood pressure; DA Vmax ¼ ductus arteriosus peak velocity; E/A ¼ early passive to late atrial contractile phase of transmitral filling ratio; LA:Ao ¼ left atrium to aortic; MAP ¼ mean airway pressure; nCPAP ¼ nasal continuous positive airway pressure; NEC ¼ necrotizing enterocolitis; OI ¼ oxygenation index; PDA ¼ patent ductus arteriosus.

ECHOCARDIOGRAPHIC GUIDANCE
Comprehensive PDA ultrasound assessment and careful transthoracic echocardiographic (TTE) guidance during the procedure is fundamental to procedural success and allows minimizing the use of both X-ray and intravenous contrast in this very fragile population.
The procedure can be entirely directed by ultrasound, by providing real-time imaging of the guidewire and catheter advancement within the heart.
Prior to commencing the procedure, a final echocardiogram assists in determining the optimal echocardiographic window, which can be difficult particularly in preterm infants requiring high frequency ventilation or those with severe bronchopulmonary dysplasia.Meticulous measurement of the PDA minimal ductal diameter and length is essential to selecting the appropriate device (Figure 3).
Echocardiographic guidance for device positioning relies on a high parasternal view.A satisfactory result is defined by an intraductal device position, no residual peri-device shunt, no device-related left pulmonary artery (LPA) obstruction (LPA peak velocity <2.5 m/s), and no device-related descending aortic obstruction (descending aorta, DAo peak velocity <2.5 m/s) (Figure 3). 6llowing device release, careful TTE assessment verifies procedural success and ensures the absence of new-onset or worsening tricuspid regurgitation or pericardial effusion.

ANESTHESIA
Although small, an ELBW infant requires substantial space in the catheterization laboratory to accommodate the ventilator and other neonatal equipment.
The anesthetic management is based on four main objectives: 1) effective sedation and analgesia, which is commenced before patient transportation to the procedure room and adjusted accordingly during the procedure; 2) careful continuous monitoring of nearinfrared spectrometry, pre-and post-ductal oxygen saturations, electrocardiogram, noninvasive blood pressure, esophageal temperature, and end-tidal carbon dioxide; 3) safe patient transport from the NICU to the catheterization laboratory, keeping in mind that even short distances within the hospital pose risks such as hypothermia, loss of vascular access, disruption of medication infusions, or accidental extubation for ELBW infants. 11,12It is thus paramount to be adequately prepared as a team, with an emergency kit and back-up equipment; 4) prevention of hypothermia, of which ELBW infants are vulnerable due to their high surface area to body weight ratio as well as the lack of an insulating fat layer.Hypothermia may expose to hypoglycemia, metabolic acidosis, pulmonary hypertension, and hypoperfusion of vital organs.Mitigating hypothermia is based on well-defined good-practice interventions, 14 that is, pre-emptive heating, continuous central temperature monitoring by an esophageal probe, and appropriate measures to avoid cooling such as warm blankets and covering the patient (Figure 4).The procedure should only be commenced once the patient is stable and all equipment is secured.

DEVICE SELECTION
PDA coil occlusion was successfully reported in 2007 in a historical series of 10 preterm infants with a procedural weight between 1,600 and 2,650 g; 15 it has gradually been superseded by a few devices which have been successfully used in closing preterm PDAs, including the AVP-II, [16][17][18] the AVP IV (Abbott), 19 the micro vascular plug (Medtronic), 20 the Micro Plug Set (Micro Plug, KA Medical), 21,22 and the Amplatzer Duct Occluder II Additional Sizes renamed the APO after the pivotal US clinical trial. 23Technical characteristics and potential drawbacks of the available devices are summarized in Table 3.The length of the AVP-II, AVP-IV, and MVP may be a limiting factor in increasing the risk of DAo and/or LPA obstruction.Moreover, the MVP, comprised of a nitinol framework partially   some operators give 50 to 100 U/kg of unfractionated heparin as a bolus once access has been achieved, 23,25 whereas others only use heparinized saline to flush the catheters before insertion with no direct administration of heparin into the patient. 24,25ocedural steps are standardized and streamlined to minimize operative time as much as possible.
Although there are significant variations in practice across centers, device closure of PDA in ELBW infants differs from that in infants weighing over 2 kg and older patients in the following aspects which are standardized worldwide: 1) the device is positioned and delivered from the venous side, using materials of the smallest size feasible; 2) no arterial access is obtained; 3) complete hemodynamic work-up is not routinely performed to shorten the procedure time and minimize catheter manipulation in these vulnerable patients; 4) procedural guidance relies heavily on TTE to minimize radiation exposure, given the increased radiosensitivity of young infants, higher heart rates, smaller cardiovascular structures, and smaller body size, all of which remain specific challenges.Despite adhering to the ALARA (As Low As Reasonably Achievable) concept, there is still a risk of relatively high radiation doses to the patient and the potential to develop radiation-related sequelae, including increased standardized incidence ratios for all-cancer, leukemia, lymphoma, and solid cancers compared with the general population; 26 5) a limited use of contrast through the catheter placed in the

PROCEDURAL EARLY OUTCOMES
Transcatheter PDA occlusion in premature infants weighing #2,000 g using the APO device has been reported to be highly effective with a success rate exceeding 98% in recent large-scale series, including the multicenter American prospective trial (N ¼ 100, procedural weight: 1,250 AE 350 g, success rate: 99%), 23 the multicenter French cohort study (N ¼ 102, procedural weight: 1,543 AE 698 g, success rate: 99%), 24 and a multicenter international study (N ¼ 68, procedural weight: 1,200 AE 370 g, success rate: 98%). 25ELBW infants did not experience post-PDA ligation syndrome after transcatheter PDA occlusion. 31Additionally, they demonstrated faster respiratory improvement and shorter mechanical ventilation, 18,26,32 as well as less major complications and less overall mortality 31 when compared to matched cases with surgical PDA ligation by posterior thoracotomy.Preterm infants were discharged home earlier than matched surgical cases when device closure is performed before the fourth week of age. 26 has however been suggested that the surgical minimally-invasive approach by anterior minithoracotomy may provide equivalent safety and efficacy than device PDA closure in ELBW and VLBW infants. 33 review of published studies with >20 cases of transcatheter PDA closure in ELBW infants, to avoid considering complications related to the learning curve, procedure-related mortality is very low (Table 4) (1/347 patients, 0.3% mortality rate) and possibly associated with the learning curve in historical series.In 2017, Morville et al. reported one procedural death out of 32 patients, due to cardiac perforation in a 680-g infant. 3435,36 Procedure-related MAE consist of device embolization (2.3%, percutaneous device retrieval in all cases), device-induced aortic obstruction (1.4%), device-induced LPA obstruction (2.0%), and cardiovascular injury (0.9%) (Table 4). 294][25] The incidence of new onset or worsening tricuspid valve regurgitation in <2 kg infants was 5% in the premarket trial 23 and 4.1% in the French multicenter study. 24The most common cause of tricuspid regurgitation is injury to the chordae of the septal leaflet of the tricuspid valve, which may be damaged during the catheter course across the valve.The incidence, mechanisms, and guidelines for the prevention and management of major procedural complications have been summarized in a recent expert consensus statement. 6vice-related complications and algorithms for the management of device-induced left pulmonary obstruction or aortic obstruction are summarized in Table 5 and Figure 5, respectively.

MID-TO LONG-TERM OUTCOMES
Regular TTE follow-up is paramount to exclude any delayed device protrusion and to monitor LPA and descending aortic flow velocities.In the absence of significant, progressive device-induced vascular    Use the esophageal temperature probe as a fluoroscopic landmark of the aortic isthmus in infants <2 kg.Consider deploying the aortic disc within the PDA rather than in the DAo to avoid protrusion of its superior edge in the aortic lumen.
Refer to management algorithm (Figure 4) Adapted from Sathanandam et al. 6 ACT ¼ activated coagulation time; DAo ¼ descending aorta; LPA ¼ left pulmonary artery; MPA ¼ main pulmonary artery; PDA ¼ patent ductus arteriosus; RA ¼ right atrium; RPA ¼ right pulmonary artery; RV ¼ right ventricle; TTE ¼ transthoracic echocardiography.procedural weight <2,000 g. 38 Of the 7 patients weighing <2,000 g who died following device implantation, no deaths were attributed to the device or procedure following an independent review by the clinical events classification committee.Beyond 6 months, there were no additional device or procedure-related complications reported.Importantly, worsening of postprocedural tricuspid regurgitation was observed in 5 ELBW (5/100, 5%) with 2 cases classified as severe; however, no intervention was required. 38

FUTURE DIRECTIONS
Transcatheter PDA closure is likely to become available to a larger number of preterm ELBW infants.As catheters and delivery systems become increasingly scaled-down in size, it is anticipated that further improvements, including additional FDA-approved devices and fluoroscopy-free percutaneous approaches, will continue to improve the safety and efficacy of transcatheter PDA closure in ELBW infants.Device PDA Closure in Premature Infants pulmonary artery MAE = major adverse events MVP = Micro Vascular Plug NEC = necrotizing enterocolitis NICU = neonatal intensive care unit PDA = patent ductus arteriosus TTE = transthoracic echocardiography VLBW = very low birth weight Baruteau et al J A C C : A D V A N C E S , V O L . 3 , N O . 1 0 , 2 0 2 4 Device PDA Closure in Premature Infants O C T O B E R 2 0 2 4 : 1 0 1 2 1 1 CENTRAL ILLUSTRATION Transcatheter Closure of Hemodynamically Significant Patent Ductus Arteriosus in Extremely Low-Birth-Weight Infants Baruteau A-E, et al.JACC Adv.. 2024;3(10):101211.ELBW ¼ extremely low-birth-weight; IVC ¼ inferior vena cava; PA ¼ pulmonary artery; PDA ¼ patent ductus arteriosus; RA ¼ right atrium.

FIGURE 1 4
FIGURE 1 Pathophysiology and Clinical Consequences of a Hemodynamically Significant Patent Ductus Arteriosus in an Extremely Low-Birth-Weight Infant

TABLE 1
Clinical and Echocardiographic Criteria for Determining the Magnitude of a ) episodes of oxygen desaturation, bradycardia, or apnea Need for respiratory support (nCPAP) or mechanical ventilation (MAP <8) Feeding intolerance (>20% gastric aspirates) Radiologic evidence of increased pulmonary vasoreactivity C3 Moderate Oxygenation difficulty (OI 7-14) Frequent (hourly) episodes of oxygen desaturation, bradycardia, or apnea Increasing ventilation requirements (MAP 9-12) Inability to feed due to marked abdominal distension or emesis Oliguria with mild elevation in plasma creatinine Systemic hypotension (low mean or diastolic BP) requiring a single cardiotropic agent Radiological evidence of cardiomegaly or pulmonary edema Mild metabolic acidosis (pH 7.1-7.25 and/or base deficit À7 to À12.0) C4 Severe Oxygenation difficulty (OI >15) High ventilation requirements (MAP >12) or need for high-frequency modes of ventilation Profound or recurrent pulmonary hemorrhage NEC-like abdominal distension with tenderness or erythema Acute renal failure Hemodynamic instability requiring >1 cardiotropic agent Moderate to severe metabolic acidosis (pH <7.1 or base deficit >À12.0)Echocardiographic Criteria E1 No evidence of ductal flow on 2-dimensional or Doppler interrogation E2 Small nonsignificant ductus arteriosus Transductal diameter <1.5 mm Restrictive continuous transductal flow (DA Vmax >2.0 m/s) No signs of left heart volume loading (eg, LA:Ao ratio >1.5:1)No signs of left heart pressure loading (eg, E/A ratio >1.0)Normal end-organ diastolic flow in superior mesenteric artery, middle cerebral artery, or renal artery E3 Moderate hemodynamically significant PDA Transductal diameter 1.5-3.0mm Unrestrictive pulsatile transductal flow (DA Vmax <2.0 m/s) Mild to moderate left heart volume loading (eg, LA:Ao ratio 1.5-2:1) Mild to moderate left heart pressure loading (eg, E/A ratio >1.0) Decreased or absent end-organ diastolic flow in superior mesenteric artery, middle cerebral artery, or renal artery E4 Large hemodynamically significant PDA Transductal diameter >3.0 mm Unrestrictive pulsatile transductal flow Severe left heart volume loading (eg, LA:Ao ratio >2:1) Device PDA Closure in Premature Infants covered by a polytetrafluoroethylene membrane at the proximal portion, exhibits low radio-opacity making visualization difficult.24The Micro Plug is a new microcatheter-delivered device with promising safety and efficacy reported in a single-center series of 25 patients,22 although this device is not yet commercially available in the European market.The APO is currently the only dedicated device available for this procedure; it has a particular design for both the fetal duct morphology and the nonelongated tubular ductus with a narrowing on the pulmonary side (Hockey stick morphology).It has been Conformité Européenne-marked and FDA-approved for use in $700 g and day $3 of life premature infants with a ductal length $3 mm and a minimal ductal diameter #4 mm.It is a self-expandable, nitinol mesh device with a central cylindrical waist and low-profile retention discs on both ends that are marginally larger than the waist, resulting in a nearly isodiametric device.The device comes pre-loaded on a delivery cable and can be delivered through a 4-F Amplatzer TorqVue LP catheter (Abbott Structural Heart).The APO is available in nine sizes comprised of three waist diameters (3, 4, and 5 mm) and three lengths (2, 4, and 6 mm).PROCEDURE DESCRIPTION Transcatheter PDA closure is usually performed in the catheterization laboratory under general anesthesia, with the patient connected to their own ventilator.The procedure is performed with both biplane fluoroscopy and TTE guidance.A 4-F sheath is inserted in the femoral vein, under ultrasound guidance to reduce the risk of access complications, particularly inadvertent puncture of the femoral artery.Prophylactic antibiotics are administered.There is no consensus on prophylactic heparin administration:

FIGURE 2
FIGURE 2 Patient Clinical Pathway for Case Planning

FIGURE 3 6 A
FIGURE 3 Ultrasound Guidance of Transcatheter PDA Closure in ELBW Infants

FIGURE 4
FIGURE 4 Prevention of Hypothermia

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A C C : A D V A N C E S , V O L . 3 , N O . 1 Device PDA Closure in Premature Infants obstruction in the early post-procedure period, mild increase in LPA and DAo flow velocities (Vmax <2.5 m/s) tend to improve spontaneously and normalize in long-term follow-up. 37Delayed occurrence of device-induced, clinically significant aortic coarctation has been reported in ELBW, underlining the importance of closely monitoring of the DAo flow velocity at least up to the end of the first month after device implantation. 30Longer term follow-up data is provided by the U.S. multicenter prospective study (NCT03055858), in which overall patient survival at 3 years was 92.9% in the 100 patients who had a

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A C C : A D V A N C E S , V O L . 3 , N O . 1 0 , 2 0 2 4 Device PDA Closure in Premature Infants O C T O B E R 2 0 2 4 : 1 0 1 2 1 1 Developing a fluoroscopy-free intervention at the patient's bedspace, without angiography and with echocardiographic guidance only would be a major step forward in the management of these extremely preterm infants, in whom the benefit-risk balance would be in favor of avoiding the potential risks associated with both radiation and contrast use.device PDA closure on 3 premature infants, although the approach for device deployment was retrograde arterial in these cases.Bedside transcatheter PDA closure solely guided by echocardiography within the neonatal intensive care unit environment has also been successfully reported in a 790 g ELBW infant40 and in a consecutive series of 11 premature infants between 800 and 1,600 g.13If demonstrated to be safe and effective in larger patient cohorts, this new technique, which eliminates both radiation and the need to transport these fragile patients to the catheterization laboratory, could emerge as the foundation for a new gold standard for PDA closure in preterm infants.

FIGURE 5
FIGURE 5 Management Algorithm for Device-Induced Left Pulmonary Artery or Aortic Obstruction

TABLE 2
Indications and Contraindications for Transcatheter PDA Closure in Extremely Low-Birth-Weight Infants PA ¼ left pulmonary artery; PDA ¼ patent ductus arteriosus.

TABLE 3
Used Devices for PDA Closure in ELBW Infants Additional sizes exist but are not suitable for PDA closure in ELBW infants.APO ¼ Amplatzer Piccolo Occluder; AVP-II ¼ Amplatzer Vascular Plug-II; AVP-IV ¼ Amplatzer Vascular Plug-IV; DAo ¼ descending aorta; MVP ¼ micro vascular plug; LPA ¼ left pulmonary artery; PDA ¼ patent ductus arteriosus. a

TABLE 4
29ocedural Safety of Transcatheter Patent Ductus Arteriosus in <2,000 g Premature Infants Using the Amplatzer Piccolo Occluder Studies were selected if >20 cases had antegrade delivery of an Amplatzer Piccolo Occluder.The Amplatzer Piccolo Occluder is the only device reported in Table1, because this is currently the only minimally invasive PDA closure device that is FDA-approved and CE-marked for premature infants.Adapted from Baruteau et al.29a Cardiac tamponade.AE ¼ clinically relevant, procedure-related adverse event.